Eric C. Lai: Notch Signaling

Notch signal transduction

Coordinated development requires that cells communicate with each other. This is made possible by molecular mechanisms of cell-cell signaling, by which cells can influence each other's fate and behavior.

A cell signaling mechanism of fundamental importance to animal development is the Notch pathway (Figure 1).

It may be safely said that Notch signaling is required, in some reasonably direct fashion, for the development of most tissues in all animal species. As such, misregulation of Notch signaling underlies a variety of human diseases and cancers.

Many ways to use a pathway

We focus on a few developmental settings that are paradigms of Notch-regulated events. One broad category is “inhibitory” signaling, whereby Notch prevents a cell from adopting a particular cell fate, usually through the repression of celltype-specific determinants. For example, Notch signaling singles out individual neural precursors from clusters of cells with neural potential.

For instance, Notch signaling specifies the wing margin, a line of cells that organizes the patterning and outgrowth of the wing proper. Loss of Notch signaling here results in loss of wing tissue (Figure 2, bottom).

Ubiquitin ligases activate DSL ligands and Notch signaling

We previously characterized two ubiquitin ligases, Neuralized and D-Mindbomb, which are absolutely required for inhibitory and inductive Notch signaling in flies, respectively. These unrelated ubiquitin ligases have a common ability to ubiquitinate both fly DSL ligands, Delta and Serrate. This modification induces DSL ligand endocytosis (Figure 3) and activates DSL signaling capacity. We are continuing to study how these ubiquitin ligases recognize DSL ligands, and how ligand endocytosis activates DSL signaling. We are also studying the regulation of these regulators, including their transcriptional and post-translational control. In particular, deployment of neuralized is highly spatially regulated. We have defined minimal enhancers that direct various aspects of neuralized transcription, and seek to define the trans-acting factors that control these enhancers.

cell (sel)

The individual unit that makes up the tissues of the body. All living things are made up of one or more cells.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

cell-cell signaling (sel-sel SIG-nuh-ling)

The transfer of information from one cell to another. Cells signal each other by direct contact with each other or by the release of a substance from one cell that is taken up by another cell. Cell-cell signaling is important for cells to grow and work normally. Cells that lose the ability to respond to signals from other cells may become cancer cells. Also called cell-to-cell signaling and intercellular communication.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

differentiation (DIH-feh-REN-shee-AY-shun)

In cancer, refers to how mature (developed) the cancer cells are in a tumor. Differentiated tumor cells resemble normal cells and tend to grow and spread at a slower rate than undifferentiated or poorly differentiated tumor cells, which lack the structure and function of normal cells and grow uncontrollably.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

margin (MAR-jin)

The edge or border of the tissue removed in cancer surgery. The margin is described as negative or clean when the pathologist finds no cancer cells at the edge of the tissue, suggesting that all of the cancer has been removed. The margin is described as positive or involved when the pathologist finds cancer cells at the edge of the tissue, suggesting that all of the cancer has not been removed.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

neural (NOOR-ul)

Having to do with nerves or the nervous system, including the brain and the spinal cord.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

tissue (TIH-shoo)

A group or layer of cells that work together to perform a specific function.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)

transcription (tran-SKRIP-shun)

In biology, the process by which a cell makes an RNA copy of a sequence of DNA that is a gene.

Source: The National Cancer Institute's Dictionary of Cancer Terms(http://www.cancer.gov/dictionary)